氧化新喹对CTX·5FU的增效作用实验研究

氧化新喹(Neoquinoxide)是1979年合成的新型化合物。对本品的机理研究与临床验证均显示对CTX·5FU有增效作用。本文进一步通过对小鼠S—180移植瘤治疗观察到,氧化新喹50mg～100mg/kg灌胃或5FU 10mg/kg腹腔注射均为无抑瘤率剂量,但组织学有变性、水肿及坏死。而同样剂量两者合用,却使抑瘤率增至38.7％。而CTX 10mg/kg腹腔注射的抑瘤率仅为25.03％,若与氧化新喹合用可提高到38.4％及48.3％。透射电镜並观察到增效组的肿瘤细胞有严重的变性、水肿、出血、坏死及自溶现象,且均明显严重过于单一用药各组的改变。特别是加用氧化新喹的各组都可观察到具有直接杀伤瘤细胞的T淋巴细胞及其明显的浸润现象。提示氧化新喹可能有增强细胞免疫活性的作用。     

库拉索芦荟多糖和木立芦荟多糖体内抗肿瘤作用

目的探讨高纯度库拉索芦荟多糖及木立芦荟多糖的抗肿瘤作用及其与5-FU的协同作用。方法常规复制S180荷瘤小鼠模型,造模后24h给药,以5-FU做为阳性对照,观察25mg/（kg.d）库拉索芦荟多糖、木立芦荟多糖、5-FU＋库拉索芦荟多糖、5-FU＋木立芦荟多糖的抗肿瘤作用,连续给药10d后,检测各组药物的抑瘤率及联合用药的协同指数。结果25mg/（kg.d）库拉索芦荟多糖和木立芦荟多糖的抑瘤率分别为45.48%、47.68%;5-FU＋库拉索芦荟多糖及5-FU＋木立芦荟多糖联合用药组的抑瘤率则分别为66.00%和62.65%,协同指数分别为0.91、0.85。结论两种芦荟多糖均可有效的抑制肿瘤生长,和5-FU相似。两种芦荟多糖与5-FU联合用药具有明显的协同作用。     

二甲双胍与消渴热清丸合用对模型大鼠胰岛素抵抗的影响

目的:研究二甲双胍与消渴热清丸合用对模型大鼠胰岛素抵抗的影响。方法:选取体重180～200g的雄性Wistar大鼠60只,随机均分为正常对照、模型、二甲双胍、消渴热清丸和二甲双胍+消渴热清丸组。各组大鼠给药第6周后,取血分别检测空腹血糖(FBG)、血清胰岛素(FIns)、血清游离脂肪酸(FFA)、血清肿瘤坏死因子-α(TNF-α)水平与胰岛素敏感性指数(ISI)。结果:经10%果糖水喂养5周后,模型组大鼠FBG、FIns、FFA、TNF-α均较正常对照组显著增高(P<0.01),ISI较正常对照组显著降低(P<0.01),大鼠有明显的胰岛素抵抗;各给药组大鼠上述各项指标与模型组比较显著降低(P<0.01或P<0.05),胰岛素敏感指数显著升高(P<0.01);且二甲双胍+消渴热清丸组比单独给予二甲双胍的大鼠效果更好。结论:二甲双胍与中药复方消渴热清丸合用有明显的协同作用,并且能在剂量上降低西药二甲双胍的用量,从而减轻二甲双胍的毒副作用。     

Metabolomic strategy to study therapeutic and synergistic effects of tanshinone IIA, salvianolic acid B and ginsenoside Rb1 in myocardial ischemia rats

Aim of the study

Tanshinone IIA (T), salvianolic acid B (S) and ginsenoside Rb1 (G) are the three major active ingredients of Compound Danshen Formula (CDF) for its protective effects on myocardial ischemia (MI). In this study, we aimed to investigate therapeutic and synergistic effects of TSG (combination of T, S and G) on MI rats with metabolomic strategy.

Materials and methods

MI model were induced in Sprague-Dawley rats by left anterior descending coronary artery ligation. MI rats were respectively administrated T, S, G, TSG and CDF. Plasma was analyzed by ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Partial least squares discriminate analysis (PLS-DA) models were built to evaluate the therapeutic and synergistic effects of TSG at whole level. 22 MI biomarkers in rat plasma were also investigated to explain that.

Results

TSG brings nearly equal therapeutic effects on MI as CDF and it plays more stable regulated action on those 22 identified metabolites than single compound.

Conclusions

Overall, there were few methods for the study of synergistic effects of Chinese medicine. Our results suggested that metabolomics offers a new idea for Chinese medicine research.     

Evaluation of long-term co-administration of tobramycin and clarithromycin in a mature biofilm model of cystic fibrosis clinical isolates of Pseudomonas aeruginosa

Pseudomonas aeruginosa colonisation and chronic lung infection associated with biofilm formation is a major cause of morbidity and mortality in cystic fibrosis (CF) patients. There is thus an urgent need to develop alternative ways to treat biofilm-associated clinical infections. A kinetic study of twice-daily co-administration of the antibiotics tobramycin and clarithromycin was performed over 28 days on 12-day-old mature P. aeruginosa biofilms formed on microplate pegs for 23 clinical isolates of various phenotypes and genotypes to simulate the treatment of CF patients with inhaled tobramycin through aerosolisation (TOBI^®). Drug activity was assessed by enumeration of persistent bacteria before, during and after treatment. A mature (12-day-old) biofilm model was chosen because a previous study suggested that such a biofilm was a more realistic in vitro model than a 24-h-old biofilm. Synergistic activity of the drug combination was confirmed on biofilms of 9/23 P. aeruginosa isolates. Of these nine isolates, total destruction of the biofilm was observed for five of them. Combination treatment was superior or equivalent to treatment with tobramycin alone, as activity was observed on 47.8% of the isolates with the combination versus 26.1% with tobramycin alone. No correlation was observed between drug susceptibility profiles and the phenotype or genotype of the isolates.     

增效灭鼠剂对大鼠作用机制研究及中毒鼠病理学观察

目的研究增效灭鼠剂的增效作用机制,并观察实验性增效灭鼠剂对鼠类中毒后病理组织变化,为提高灭鼠效果和应用提供依据。方法以SD大鼠为模型,检测增效灭鼠剂对大鼠凝血时间（CT）、凝血酶原时间（PT）、部分凝血酶原时间（APTT）和纤维蛋白原（FIB）的影响,采用石蜡切片和HE染色技术观察大鼠实验性增效灭鼠剂中毒后的组织病理变化。结果单独增效剂能引起大鼠CT、APTT延长以及FIB的增加;杀鼠迷组与增效杀鼠迷组CT、PT、APTY均显著延长,FIB显著减少;相对于杀鼠迷组,增效杀鼠迷组CT、PT、APTT显著延长,FIB减少。中毒鼠内脏病理学观察发现,增效灭鼠剂能引起更大程度的胃肠表面黏膜破坏而导致溃疡,肺静脉血管出现破裂及肝组织损伤坏死。结论增效剂本身具有抗凝血功能,同浓度的增效杀鼠迷组比杀鼠迷组具有更强的抗凝血功能;增效灭鼠剂导致鼠类内出血并引起肝脏损伤,进一步阻碍肝脏凝血功能和其他正常生理功能,而增效剂本身并不会造成组织病理损伤。     

Synergistic effect of galantamine with risperidone on impairment of social interaction in phencyclidine-treated mice as a schizophrenic animal model

Social withdrawal is the first sign and key component of the negative symptoms of schizophrenia. The efficacy of risperidone, an atypical antipsychotic, on the symptom is practically limited by dose-dependent side effects in clinical trials, therefore there is the need for adjuvant treatments. In the present study, we aimed to investigate the synergistic effect and mechanism of risperidone and galantamine, which is a nicotinic acetylcholine receptor (nAChR)-allosteric modulator and a modest cholinesterase inhibitor, on phencyclidine (PCP)-treated mouse model of social withdrawal. At non-effective doses by themselves, co-administration of galantamine (0.05mg/kg) and risperidone (0.05mg/kg) showed synergistic effects on PCP-induced impairments of social interaction and dopamine release in the medial prefrontal cortex (mPFC). The behavioral synergistic effect was abolished by the administration of a dopamine-D(1) receptor antagonist, SCH 23390 (0.02mg/kg, systemic; or 0.02microg/0.5microL/mouse, intra-mPFC), and a nAChR antagonist, mecamylamine (3mg/kg), but not a muscarinic receptor antagonist, scopolamine (0.1mg/kg). Mecamylamine (3mg/kg) also abolished the synergistic effect on dopamine release in the mPFC. We conclude that galantamine may have synergistic effect with risperidone on the negative symptom of social withdrawal in schizophrenia, which is mediated by dopamine-D(1) receptors in the mPFC through nAChR activation-increased dopamine release.     

Evolution and development of potent monobactam sulfonate candidate IMBZ18g as a dual inhibitor against MDR Gram-negative bacteria producing ESBLs

A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria. Compound 33a (IMBZ18G) is highly effective in vitro and in vivo against clinically intractable multi-drug-resistant (MDR) Gram-negative strains, with a highly druglike nature. The checkerboard assay reveals its significant synergistic effect with β-lactamase inhibitor avibactam, and the MIC values against MDR enterobacteria were reduced up to 4–512 folds. X-ray co-crystal and chemoproteomic assays indicate that the anti-MDR bacteria effect of 33a results from the dual inhibition of the common PBP3 and some class A and C β-lactamases. Accordingly, preclinical studies of 33a alone and 33a‒avibactam combination as potential innovative candidates are actively going on, in the treatment of β-lactamase-producing MDR Gram-negative bacterial infections.     

Effectiveness of a double-carbapenem combinations against carbapenem-resistant Gram-negative bacteria

The emergence of carbapenem-resistant organisms posed considerable threat to global health while only limited treatment options are available and led to efforts to discover a novel way to treat them. To evaluate in vitro synergistic activity of meropenem plus ertapenem, a total of 203 carbapenem-resistant strains, collected from 12 provinces and municipalities in China, were examined with a dual carbapenem combination therapy. The statistical software R was used for analysis. Two hundred and one (201) of carbapenem-resistant strains mainly produced four types of carbapenemase: KPC-2 (n = 142, 69.95%), OXA-232 (n = 7, 3.45%), NDM (n = 38, 18.72%; 36 NDM-1, 1 NDM-4, 1 NDM-5), and IMP (n = 15, 7.39%; 1 IMP-26, 10 IMP-30, 4 IMP-4). Fifty-one out of two hundred and three (51/203 or 25.12%) of the examined strains showed a synergistic effect for the meropenem plus ertapenem combination throughout the checkerboard method, while only three isolates showed potential clinically relevant synergy (3/203, 1.48%). An additive effect was observed in 55/203 (27.09%) of the examined strains. Ninety-seven of the examined isolates (47.78%) showed fractional inhibitory concentration (FIC) greater or equal to 2 (indicating antagonism). The synergistic activity of meropenem plus ertapenem combination suggests this combination can be a possible way to treat the infection caused by the carbapenem-resistant organisms, especially for IMP or NDM producer with a lesser minimum inhibitory concentration (MIC) and the infected individual who was not recommended to use colistin or tigecycline.     

丹参联合葛根对糖尿病眼病模型大鼠的协同作用

目的:研究丹参联合葛根对糖尿病眼病模型大鼠的协同作用。方法:腹腔注射链脲佐菌素-弗氏完全佐剂联合喂饲高脂饲料以复制大鼠糖尿病眼病模型。实验分为正常对照(等容生理盐水)组、模型(等容生理盐水)组、葛根(33 g/kg)组、葛根丹参(33 g/kg+33 g/kg)组,灌胃给药,每天2次,连续15 d。于电镜下观察大鼠眼组织形态变化。分别灌胃葛根(33 g/kg)、葛根丹参(33g/kg+33 g/kg),给药0、10、20、30、45、60、90、120、240、360、480 min时取血,高效液相色谱法测定大鼠血浆中葛根素的血药浓度。色谱柱为Diamonsil C18(250 mm×4.6 mm,5μm),流动相为甲醇-水(25∶75,V/V),检测波长为250 nm,流速为1.0 ml/min,柱温为25Ⅸ,进样量为10μl。以WinNonlin软件分析药动学参数。结果:模型组大鼠眼组织视网膜细胞萎缩,脉络膜血管增生、扩张、充血,出现新生血芽,内皮细胞核数目增多,给药后上述病理状态均得到改善,其中葛根丹参组改善情况优于葛根组。葛根素质量浓度在0.1⁸.0 mg/ml范围内与其同内标峰面积比值呈良好线性关系,精密度试验RSD均小于3%,稳定性试验RSD均小于4%,回收率在86.02%8.0 mg/ml范围内与其同内标峰面积比值呈良好线性关系,精密度试验RSD均小于3%,稳定性试验RSD均小于4%,回收率在86.02%⁹0.28%。葛根组与葛根丹参组AUC分别为(156.49±32.62)、(462.27±119.86)mg·min/L,cmax分别为1.426 5、1.986 2 mg/ml,t1/2kα分别为(9.62±1.59)、(10.07±2.11)min。结论:丹参与葛根配伍,可明显促进葛根素的体内吸收、分布,减缓其消除,促进葛根素在血液中的富集且能改善模型大鼠眼组织病变。丹参对葛根改善模型大鼠糖尿病眼病具有较好协同增效作用。